The Role of Osteopontin in Macrophage Infiltration into Injured Liver.

骨桥蛋白在巨噬细胞浸润受损肝脏中的作用。

基本信息

  • 批准号:
    11670529
  • 负责人:
  • 金额:
    $ 2.3万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    1999
  • 资助国家:
    日本
  • 起止时间:
    1999 至 2000
  • 项目状态:
    已结题

项目摘要

Macrophage infiltration into the liver is assumed to be a critical event in the development of fulminant hepatic failure, since massive liver necrosis can develop as a result of microcirculatory disturbance due to sinusoidal fibrin deposition caused by activated macrophages. However, the precise mechanisms of such macrophage infiltration are to be elucidated. Osteopontin, an extracellular matrix with RGD sequence, has been shown to act as a chemokine that can induce macrophage migration. The possibility that osteopontin can play a role in infiltration of macrophages into the liver was investigated in rats and mice. Northern blot analysis revealed that osteopontin mRNA expression was minimal in Kupffer cells and hepatocytes immediately after isolation from normal rats, but slight in stellate cells cultured for 3 days on plastic dishes. When rats received carbon tetrachloride or heat-killed Propionibacterium acnes (P.acnes), osteopontin mRNA expression assessed by competitive RT-PCR was … More increased in the liver preceding the occurrence of macrophage infiltration. Kupffer cells and hepatic macrophages and stellate cells isolated from such liver showed marked expression of osteopontin mRNA on Northern blotting. Immunohistochemical examination disclosed that osteopontin was stained in the Golgi apparatus of macrophages including Kupffer cells and hepatic stellate cells in these rats. In P.acnes-treated rats, both mRNA expressions of MIC-1 and MIP-1α were increased in the liver. Although mice with allele B osteopontin gene, in which osteopontin expression was absent, showed similar increase of both chemokine expressions, hepatic macrophage infiltration was minimal in such mice following P.acnes administration. Osteopontin may play a central role in hepatic macrophage infiltration among various chemokines. Kupffer cells and hepatic macrophages and stellate cells may contribute to hepatic macrophage infiltration by expressing osteopontin.Regulation mechanisms of osteopontin expression in the liver were examined using rat stellate cells and hepatocytes in primary culture. In both cells, mRNA and protein expressions of osteopontin were upregulated following stimulation by TGF-β in a dose-dependant manner. Immunohistochemical examination revealed that osteopontin was expressed in hepatocytes and stellate cells in the liver of patients with liver cirrhosis. Also, the expression was found in well-differentiated hepatocellular carcinoma cells in these patients. Thus, osteopontin might be involved in the process of liver fibrosis and carcinogenesis as well as massive liver necrosis. To clarify the role of osteopontin in the development of liver diseases, we established transgenic mice expressing osteopontin abundantly in the liver. Less
巨噬细胞浸润到肝脏中被认为是暴发性肝衰竭发展中的关键事件,因为由于活化的巨噬细胞引起的窦状纤维蛋白沉积导致的微循环障碍可导致大面积肝坏死。然而,这种巨噬细胞浸润的确切机制有待阐明。骨桥蛋白是一种具有RGD序列的细胞外基质,已被证明是一种可诱导巨噬细胞迁移的趋化因子。在大鼠和小鼠中研究了骨桥蛋白在巨噬细胞向肝脏浸润中发挥作用的可能性。北方印迹分析显示,骨桥蛋白mRNA在正常大鼠枯否细胞和肝细胞分离后立即表达最低,而在塑料培养皿上培养3天的星状细胞中表达最低。当大鼠接受四氯化碳或热灭活的痤疮丙酸杆菌(P.acnes)时,通过竞争性RT-PCR评估的骨桥蛋白mRNA表达, ...更多信息 在巨噬细胞浸润发生之前,肝脏中的浓度增加。北方印迹法显示,枯否细胞、肝巨噬细胞和星状细胞均表达骨桥蛋白mRNA。免疫组化结果显示,骨桥蛋白在巨噬细胞(包括枯否细胞和肝星状细胞)的高尔基体中染色。在痤疮丙酸杆菌处理的大鼠中,MIC-1和MIP-1α的mRNA表达均增加。尽管骨桥蛋白基因等位基因B小鼠(其中骨桥蛋白表达缺失)显示出两种趋化因子表达的相似增加,但在给予痤疮丙酸杆菌后,此类小鼠的肝巨噬细胞浸润最小。骨桥蛋白可能在多种趋化因子中对肝巨噬细胞浸润起重要作用。Kupffer细胞、肝巨噬细胞和星状细胞可能通过表达骨桥蛋白参与肝巨噬细胞浸润,本研究采用大鼠肝星状细胞和肝细胞原代培养,探讨了骨桥蛋白在肝巨噬细胞浸润中的调控机制。在两种细胞中,骨桥蛋白的mRNA和蛋白表达在TGF-β刺激后以剂量依赖性方式上调。免疫组化结果显示,肝硬化患者肝内的肝细胞和星状细胞表达骨桥蛋白。此外,在这些患者的高分化肝细胞癌细胞中发现了表达。因此,骨桥蛋白可能参与了肝纤维化和癌变以及大面积肝坏死的过程。为了阐明骨桥蛋白在肝脏疾病发展中的作用,我们建立了在肝脏中大量表达骨桥蛋白的转基因小鼠。少

项目成果

期刊论文数量(40)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K.: "VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells."Biochem Biophys Res Commun. 280. 481-485 (2001)
Funyu J、Mochida S、Inao M、Matsui A、Fujiwara K.:“VEGF 可以通过上调内皮细胞的孔隙率作为肝窦中的血管通透性因子。”Biochem Biophys Res Commun。
  • DOI:
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  • 影响因子:
    0
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Osada N,Mochida S,Inao M,Mashimo Y,Fujiwara K.: "Apoptisis in dissociation between DNA synthesis and cellular functions of activated hepatic stellate cells : A study with carbon tetrachloride-induced rat liver injury."Biochemical Biophysical Research Comm
Osada N、Mochida S、Inao M、Mashimo Y、Fujiwara K.:“活化肝星状细胞 DNA 合成与细胞功能之间的细胞凋亡:四氯化碳诱导的大鼠肝损伤的研究。”生化生物物理研究通讯
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    0
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  • 通讯作者:
Fujiwara K, Mochida S.: "Etiology and pathophysiology of fulminant hepatic failure."Molecular Biology and Immunology for the Treatment of Intractable Liver Diseases. Tsuji T, et al. (eds), Elsevier Science, Amsterdam, (in press).
Fujiwara K、Mochida S.:“暴发性肝衰竭的病因学和病理生理学”。治疗顽固性肝病的分子生物学和免疫学。
  • DOI:
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  • 影响因子:
    0
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Ikeda H,Yatomi Y,Yanase M,Satoh H,Maekawa H,Ogata I,Ozaki Y,Takawa Y,Mochida S,Fujiwara K.: "Biological activities of novel lipid mediator sphingosine 1-phosphate in rat hepatic stellate cells."American Journal of Physiology. 279. G304-G310 (2000)
Ikeda H、Yatomi Y、Yanase M、Satoh H、Maekawa H、Ogata I、Ozaki Y、Takawa Y、Mochida S、Fujiwara K.:“新型脂质介质鞘氨醇 1-磷酸在大鼠肝星状细胞中的生物活性。”美国
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  • 影响因子:
    0
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  • 通讯作者:
Niimi Y, Mochida S, Matsui A, Inao M, Fujiwara K.: "PKC- and MAPK-independent upregulation of VEGF receptor expressions in human umbilical venous endothelial cells following VEGF stimulation."Hepatology Res. (in press).
Niimi Y、Mochida S、Matsui A、Inao M、Fujiwara K.:“VEGF 刺激后人脐静脉内皮细胞中 VEGF 受体表达的 PKC 和 MAPK 独立上调。”肝病学研究。
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    0
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MOCHIDA Satoshi其他文献

MOCHIDA Satoshi的其他文献

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{{ truncateString('MOCHIDA Satoshi', 18)}}的其他基金

Identification of Female-Specific Transcriptional Factors for Osteopontin Translation as a Host Factor to Determine the Difference of Clinical Features of Liver Diseases between Male and Female Patients
鉴定女性特异性骨桥蛋白翻译转录因子作为宿主因子,以确定男性和女性患者肝病临床特征的差异
  • 批准号:
    21590858
  • 财政年份:
    2009
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The regulatory mechanisms of osteopontin expression in as a genetic factor to determine inflammatory grading in the liver of HCV infected patients
骨桥蛋白表达作为遗传因素决定HCV感染患者肝脏炎症分级的调节机制
  • 批准号:
    19590788
  • 财政年份:
    2007
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genetic factors determining the severity of hepatitis in patients receiving hepatitis virus infection : Significance of osteopontin promoter SNPs
决定肝炎病毒感染患者肝炎严重程度的遗传因素:骨桥蛋白启动子SNP的意义
  • 批准号:
    16590628
  • 财政年份:
    2004
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The significance of Osteopontin in development of necrosis, regeneration, fibrosis and carcinogenesis in the liver : Evaluation using osteopontin transgenic mice.
骨桥蛋白在肝脏坏死、再生、纤维化和癌变发展中的重要性:使用骨桥蛋白转基因小鼠进行评估。
  • 批准号:
    14570505
  • 财政年份:
    2002
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Mechanisms of Impaired Liver Regeneration in Fulminant Hepatic Failure : The Significance of Sinusoidal Endothelial Cell Proliferation.
暴发性肝衰竭中肝脏再生受损的机制:正弦内皮细胞增殖的意义。
  • 批准号:
    09670571
  • 财政年份:
    1997
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Anticoagulant Targeting the Hepatic Sinusoids for Liver Injury Following Orthotopic Liver Transplantation
针对原位肝移植后肝损伤的肝正弦抗凝剂
  • 批准号:
    07670611
  • 财政年份:
    1995
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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M2巨噬细胞上CD206表面抗原在饮食诱导肥胖小鼠模型胰岛素抵抗发展中的作用
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    24K18516
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通过 TREM2 允许巨噬细胞分化和功能调节
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肺泡巨噬细胞和调节途径在移植后肺部炎症中的作用。
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